KR20060062359A - Biodegradable polymer film and drug film coating method for drug release stent - Google Patents

Abstract

The present invention relates to a biodegradable polymer film for drug release stents and a method for coating the polymer film, and more particularly, a biodegradable lactide / ε- having a molar ratio of lactide to ε-caprolactone of 4: 6 to 1: 9. A biodegradable polymer film for drug release stents prepared from a caprolactone copolymer and a method for coating the polymer film.

Biodegradable polymer film for drug release stent coated according to the method of the present invention is excellent in flexibility and elastic mechanical properties, and after a certain period of time after the stent treatment is biodegradable and does not require a separate removal surgery, as a stent It prevents restenosis by minimizing the inflammatory response caused, and can slowly release biologically active substances, including restenosis suppressing drugs, in the human body for long-term delivery.

Stent, lactide, ε-caprolactone, copolymer, biodegradability, tensile strength, elongation, restenosis, polymer film

Description

Biodegradable polymer film for drug release stent and method for coating the polymer film {BIODEGRADABLE POLYMER FILM FOR DRUG ELUTING STENT AND COVERING METHOD THEREOF}

1 is a graph showing the drug release form of the biodegradable polymer film for drug release stent coated by the method of Example 1 and Comparative Examples 1 to 3 of the present invention.

Figure 2 is a graph showing the drug release form of the biodegradable polymer film for drug release stent coated by the method of Example 1 and Comparative Examples 4 to 5 of the present invention.

3 is a graph showing the drug release form of the biodegradable polymer film for drug release stent coated by the method of Example 1 and Comparative Examples 6 to 7 of the present invention.

Figure 4 is a graph showing the drug release form of the biodegradable polymer film for drug release stent coated by the method of Example 1 and Comparative Examples 8 to 9 of the present invention.

The present invention relates to a biodegradable polymer film for drug release stents and a method for coating the polymer film, and more particularly, has excellent mechanical properties of flexibility and elasticity, has suitable biodegradability, and biologically active materials. The present invention relates to a biodegradable polymer film for drug release stents that can be released slowly in the human body and delivered for a long time, and a coating method thereof.

In general, due to diseases occurring in the human body, the lumen of the body may be narrowed or closed, and in this case, the function of the organ may be degraded or, in severe cases, it may become incapable of performing any function. For example, when gastrointestinal obstruction is blocked by gastric cancer, or when a part of the esophagus due to esophageal cancer is constricted, when arterial sclerosis does not allow for good blood circulation, or when the bile ducts from which the bile from the liver flows are narrowed Case and so on.

As such, when the lumen is blocked or narrowed, food, blood, or bile cannot flow smoothly to each organ, causing other symptoms and complications. Therefore, it is necessary to expand the narrowed lumen or prevent the enlarged lumen from narrowing again. As a method for expanding the constricted lumen passage and maintaining the expanded state, it is a medical tube having an open shape at both ends. Insertion of a microstructured stent into the stenosis of the lumen has been performed.

In addition, the implantation or expansion of a stent device into the esophagus, respiratory tract, blood vessels, urinary tract or other inaccessible lumen for the purpose of facilitating or restoring treatment has become a common form of treatment.

Typically, such a stent is made of a cylindrical structure having a mesh shape by twisting a metal wire having elastic force in a zigzag form, and the material itself has elastic force and can be contracted by applying an external force, such as a catheter in this state. When inserted into the lumen using a medical device is made to expand by its elasticity. The stent inserted into the lumen expands the constricted lumen while maintaining the passage of the lumen.

However, since the metal stent is an external material of the human body, an inflammatory reaction may occur, and safety may be a problem when used for a long time. In addition, the stent needs to be removed again after a certain period of time after the procedure on the lesion site, and the removal of the stent may not only cause pain and cost to the patient, but also during the insertion and removal of the stent. There is a problem that can cause an inflammatory response by injuring the artery wall. In particular, such an inflammatory response may have a problem in that the defense response of the human body is activated to cause immune cells to gather at the stent position, thereby increasing the possibility of restenosis.

For example, the Korean Patent Publication No. 10-2004-0035434 discloses a stent for overcoming the above-described problems of the metal stent and increasing biodegradability after a certain period of time after the procedure using a biodegradable film. Stents are disclosed that allow degradation and polymers or copolymers such as polylactide, polycaprolactone, etc. can be used as biodegradable films. Korean Patent Publication No. 10-2004-0050915 proposes a stent for preventing restenosis using a biodegradable polymer. However, there is no way to improve the flexibility and elasticity of the biodegradable film and to release the biologically active substance in the body properly. In addition, Korean Patent Laid-Open Publication No. 10-2004-0039351 discloses a stent having a sustained-release drug release system by coating all or part of a stent with a biodegradable polymer, and polyanhydrides, polylactic acid, and the like are exemplified as biodegradable polymers. It is. However, this also does not suggest a way to improve the mechanical properties of the biodegradable film.

In order to solve the problems as described above, an object of the present invention is to biodegrade after a certain period of time after the stent treatment does not need a separate removal surgery, it is possible to prevent restenosis by minimizing the inflammatory response due to the stent procedure It is to provide a biodegradable polymer film for drug release stents.

Another object of the present invention is to provide a biodegradable polymer film for drug release stents capable of long-term delivery by slowly releasing biologically active therapeutic substances, including restenosis inhibiting drugs.

Still another object of the present invention is to provide a biodegradable polymer film for drug release stent having excellent flexibility and elastic mechanical properties.

Still another object of the present invention is to provide a coating method of a biodegradable polymer film having the above-described physical properties.

In order to achieve the above object, the present invention is prepared from a biodegradable lactide / ε-caprolactone copolymer having a repeating unit of formula 1 and having a molar ratio of lactide to ε-caprolactone of 4: 6 to 1: 9. It provides a biodegradable polymer film for drug release stent.

[Formula 1]

(Wherein

x and y are the molar ratios of each monomer, x is 0.1 to 0.4, y is 0.6 to 0.9, x + y = 1,

n is the polymerization degree of a copolymer, 25 or more, Preferably it has a value of 25-30.)

The present invention also provides (1) a biodegradable lactide / ε-caprolactone copolymer having 5 to 10 molar ratio of lactide to ε-caprolactone having a repeating unit of Formula 1 Preparing a mixture for coating a biodegradable film comprising a weight percent, 1 to 30 weight percent of a biologically active substance and a solvent balance; (2) dip-coating the stent into the mixture for 30 to 90 seconds; And, (3) provides a biodegradable polymer film coating method for drug-release stents comprising the step of drying the dip-coated stent at room temperature for 20 to 60 hours.

Hereinafter, the present invention will be described in detail.

The present inventors have studied various biodegradable synthetic polymers to develop a biodegradable polymer film for drug release stents having excellent flexibility and elasticity and suitable biodegradability. As a result, the composition of lactide and ε-caprolactone is properly adjusted. Controlled copolymerization of lactide / ε-caprolactone copolymers complements the excellent mechanical properties of polylactide and the flexibility of polycaprolactone, resulting in excellent flexibility and elastic mechanical properties, adequate biodegradability, and biologically active materials. The present invention has been found to be suitable for long-term delivery of the present invention.

The lactide / ε-caprolactone copolymers used in the biodegradable polymer film for drug release stents of the present invention are lactide / ε-caprolactone copolymers having a repeating unit represented by the following formula (1). It is excellent and has biodegradability that decomposes itself after a certain period of time after being treated in the body.

[Formula 1]

(Wherein

x and y are the molar ratios of each monomer, x is 0.1 to 0.4, y is 0.6 to 0.9, x + y = 1,

n is the polymerization degree of a copolymer, 25 or more, Preferably it has a value of 25-30.)

The lactide / ε-caprolactone copolymers have a translucent brown color, are flexible, excellent in elasticity, and have suitable hydrolyzability, and are very useful for preparing biodegradable polymer films for drug release stents.

Suitable composition molar ratios of the monomers of the lactide / ε-caprolactone copolymers used in the present invention are 4.0 / 6.0 to 1.0 / 9.0 in terms of the lactide / ε-caprolactone molar ratio. If the lactide molar ratio of the copolymer composed of lactide / ε-caprolactone is 40% or more, cracks occur on the surface of the biodegradable polymer film for drug-release stents made of such a copolymer, which is not preferable. It is not preferable because a relatively large amount of ε-caprolactone is included in the biodegradable polymer film for drug release stents to increase the body decomposition time.

The lactide / ε-caprolactone copolymer used in the present invention can be produced by ring-opening polymerization of lactide and ε-caprolactone under reduced pressure in the presence of a polymerization catalyst. Hereinafter, the manufacturing process of the lactide / ε-caprolactone copolymer of the present invention will be described in detail.

The lactide / ε-caprolactone copolymer of the present invention having a repeating unit of Formula 1 is prepared by, for example, a copolymerization reaction as in Scheme 1 below.

Scheme 1

The ring-opening polymerization reaction is carried out by heating and decompression method using a common ring-opening polymerization catalyst. The reaction temperature is about 100 to 230 ° C, preferably about 130 to 200 ° C. The reaction time is at least about 5 hours, preferably about 5 to 50 hours.

As the catalyst used in the ring-opening polymerization reaction, in general, all known catalysts used in the ring-opening polymerization reaction of lactide and ε-caprolactone can be used. Catalysts used in the ring-opening polymerization reaction include tetraphenyltin, tin powder, tin octosan, stannous chloride, ditin tin chloride, tin oxide, zinc powder, diethylzinc, zinc octoate, zinc chloride, and zinc oxide. Etc. The amount of catalyst added is about 0.0001 to 5 mol%, preferably about 0.001 to 0.5 mol%, based on the monomer of lactide and ε-caprolactone.

The molecular weight of the polymer gradually increases after the polymerization reaction is initiated. Structural analysis and molecular weight determination of polymers are determined using hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR), differential scanning calorimetry (DSC) and gel permeation chromatography (GPC).

The tensile strength of the biodegradable polymer film for drug release stent according to the present invention is preferably 15 to 35 MPa. If the tensile strength of the biodegradable polymer film for drug release stents is less than 15 MPa, there is a problem of poor form retention of the polymer film formed on the stent, and if the tensile strength exceeds 35 MPa, cracks occur in the polymer film formed on the stent. There is this.

The elongation of the biodegradable polymer film for drug release stent according to the present invention is preferably 600 to 800%. If the elongation of the biodegradable polymer film is less than 600%, cracks may occur in the polymer film formed on the stent, which is not preferable. As form preservation is inferior Not preferred.

Biodegradable polymer film coating method for a drug release stent of the present invention,

First, 5 to 10% by weight of a biodegradable lactide / ε-caprolactone copolymer having a repeating unit of Formula 1 and having a molar ratio of lactide to ε-caprolactone of 4: 6 to 1: 9, biologically active substance 1 To prepare a biodegradable film coating mixture containing from 30 to 30% by weight and the solvent balance.

At this time, if the content of the lactide / ε-caprolactone copolymer in the mixture is less than 5% by weight, the release of the biologically active substance is excessively quick, and if it exceeds 10% by weight, the release of the biologically active substance is excessively There is a problem that it is slow to control the rate of drug release.

As the biologically active substance, anti-thrombogenic agents, anti-proliferative agents, growth factors, radiochemicals, etc. may be used as drug components. Preferably, as a drug capable of inhibiting restenosis, it may be selected from the group consisting of paclitaxel, rapamycin, dexamethasone, and actinomycin-D. . At this time, the content of the biologically active substance is suitably 1 to 30% by weight.

As the solvent used in the biodegradable film coating mixture, any solvent which is harmless to the human body while dissolving the copolymer and the biologically active substance can be used. Representative examples of the solvent include chloroform and tetrahydrofuran.

Secondly, the stent is inserted into the mixture and dip-coated for 30 to 90 seconds. If the dip coating time is less than 30 seconds, the biologically active substance is released excessively quickly in the body, and if it exceeds 10% by weight, the release time of the biologically active substance is excessively long.

Third, the biodegradable polymer film is coated on the stent by drying the dip-coated stent at room temperature for 20 to 60 hours.

Hereinafter, preferred examples and comparative examples of the present invention are described. However, the following examples are only one preferred embodiment of the present invention and the present invention is not limited to the following examples.

(Example)

(Example 1)

14.46 g of lactide and 26.64 g of epsilon -caprolactone and 0.0182 g of octosan tin were diluted with 0.128 ml of toluene as a catalyst. Teflon-coated magnetic bars were placed in the ampoules containing the reactants, and the ampoules were kept in a vacuum at 0.005 mmHg for about 2 hours to remove toluene and water.

Subsequently, dry nitrogen injection and vacuum maintenance were repeated 10 times, and the ampoule was heat-sealed. The sealed ampoules were stirred using a magnetic plate while raising the temperature to 170 ° C at 1 ° C / min in a 105 ° C oil bath. Thereafter, solid phase polymerization was performed at 170 ° C. for 24 hours. As the polymerization proceeded, the viscosity of the polymerization system increased and stirring was impossible. The polymerization system was initially a clear gel but turned to a brown solid as the reaction proceeded. After the reaction was completed, the ampoule was sufficiently cooled using liquid nitrogen, and then the ampoule was destroyed to recover the copolymer. The recovered sample was dissolved in chloroform and precipitated in methanol to remove unreacted monomer to recover the polymer. The molar ratio of the lactide / ε-caprolactone copolymer measured by hydrogen nuclear magnetic resonance analysis was 3.0 / 7.0.

Prepare a biodegradable film coating mixture comprising 7% by weight of the prepared lactide / ε-caprolactone copolymer, 1% by weight of paclitaxel and the balance of chloroform, and inserting a stent into the mixture for 60 seconds to dip coating (dip- coating). The dip-coated stent was dried for 48 hours at room temperature in a vacuum oven to coat the biodegradable polymer film on the drug release stent.

(Comparative Example 1)

The lactide / ε-caprolactone copolymer was synthesized in the same manner as in Example 1 using 41.30 g of lactide and 0.0182 g of octosan tin diluted in 0.128 ml of toluene as a catalyst.

The molar ratio of the lactide / ε-caprolactone copolymer measured by hydrogen nuclear magnetic resonance analysis was 10.0 / 0.0.

The biodegradable polymer film was coated in the same manner as in Example 1 using the prepared lactide / ε-caprolactone copolymer.

(Comparative Example 2)

The lactide / ε-caprolactone copolymer was synthesized in the same manner as in Example 1, using 34.212 g of lactide and 11.42 g of ε-caprolactone and 0.0182 g of octosan tin diluted in 0.128 mL of toluene as a catalyst. .

The molar ratio of the lactide / ε-caprolactone copolymer measured by hydrogen nuclear magnetic resonance analysis was 7.0 / 3.0.

The biodegradable polymer film was coated in the same manner as in Example 1 using the prepared lactide / ε-caprolactone copolymer.

(Comparative Example 3)

A lactide / ε-caprolactone copolymer was synthesized in the same manner as in Example 1 using 38.05 g of epsilon -caprolactone and 0.0182 g of octosan tin diluted in 0.128 mL of toluene as a catalyst.

The molar ratio of the lactide / ε-caprolactone copolymer measured by hydrogen nuclear magnetic resonance analysis was 0.0 / 10.0.

The biodegradable polymer film was coated in the same manner as in Example 1 using the prepared lactide / ε-caprolactone copolymer.

(Comparative Example 4)

The biodegradable polymer film was coated in the same manner as in Example 1 except that 3 wt% of the lactide / ε-caprolactone copolymer was used.

(Comparative Example 5)

The biodegradable polymer film was coated in the same manner as in Example 1 except that 15 wt% of the lactide / ε-caprolactone copolymer was used.

(Comparative Example 6)

The biodegradable polymer film was coated in the same manner as in Example 1 except that 0.3 wt% of paclitaxel was used.

(Comparative Example 7)

Biodegradable polymer was coated in the same manner as in Example 1, except that 3% by weight of paclitaxel was used.

(Comparative Example 8)

The biodegradable polymer film was coated in the same manner as in Example 1 except that the stent was dip-coated for 20 seconds.

(Comparative Example 9)

The biodegradable polymer film was coated in the same manner as in Example 1 except that the stent was dip-coated for 120 seconds.

division  Composition molar ratio of copolymer Biodegradable film coating mixture Copolymer (% by weight) Paclitaxel (% by weight) Immersion Coating Time (sec) Example 1 [LA] / [CL] 3.0 / 7.0 7 One 60 Comparative Example 1 [LA] / [CL] 10.0 / 0.0 7 One 60 Comparative Example 2 [LA] / [CL] 7.0 / 3.0 7 One 60 Comparative Example 3 [LA] / [CL] 0.0 / 10.0 7 One 60 Comparative Example 4 [LA] / [CL] 3.0 / 7.0 3 One 60 Comparative Example 5 [LA] / [CL] 3.0 / 7.0 15 One 60 Comparative Example 6 [LA] / [CL] 3.0 / 7.0 7 0.3 60 Comparative Example 7 [LA] / [CL] 3.0 / 7.0 7 3 60 Comparative Example 8 [LA] / [CL] 3.0 / 7.0 7 One 20 Comparative Example 9 [LA] / [CL] 3.0 / 7.0 7 One 120 LA: Lactide CL: Caprolactone

Experimental Example

Experimental Example 1

(Mechanical Properties of Polymer Films According to Copolymer Composition Molar Ratio)

The mechanical properties of the biodegradable polymer films prepared in Example 1 and Comparative Examples 1 to 3 were evaluated using a universal testing machine (Instron, Model 5567, MA) as follows. First, the prepared support was constantly cut into 10 × 10 mm specimens, and then the specimens were adhered to the fixed plate so that the measurement length was maintained at 7 mm. Tensile strength was measured at a constant rate of 1 mm / min using a 5 kg load cell. Through the tensile force-tension length graph obtained after the measurement, the elongation was obtained by measuring the tensile length up to the end point of the graph obtained in a straight line and the tensile strength was the point where the tensile force was the highest, and the measurement results are shown in Table 2 below.

Mechanical Properties of Polymeric Films According to the Composition Molar Ratio of Copolymers division  Composition molar ratio of copolymer  Tensile Strength (MPa) Elongation (%) Example 1  [LA] / [CL] 3.0 / 7.0 20.7 751 Comparative Example 1 [LA] / [CL] 10.0 / 0.0 69.1 brittle Comparative Example 2 [LA] / [CL] 7.0 / 3.0 39.4 440 Comparative Example 3 [LA] / [CL] 0.0 / 10.0 14.3 580 LA: Lactide CL: Caprolactone

As can be seen in Table 2, in the case of Comparative Examples 1 to 3, in the case of Comparative Examples 1 to 3, the composition molar ratio of the lactide / ε-caprolactone copolymer is 4: 6 to 1: 9 out of the biodegradable polymer It can be seen that the mechanical properties of flexibility and elasticity required for the film are inferior in comparison with Example 1.

Experimental Example 2

(Drug Release In Vitro Experiment with Copolymer Composition)

After bursting the coated stent in the method of Example 1 and Comparative Examples 1 to 3 into a 15 ml tube containing 1 ml of distilled water at 37 ° C. while maintaining the temperature, the drug concentration experiment was performed for up to 300 hours. Was measured.

1 is a graph showing the drug release form of the biodegradable polymer film for drug release stents prepared by the method of Example 1 and Comparative Examples 1 to 3 of the present invention. As can be seen in Figure 1, in Comparative Examples 1 to 3, the composition molar ratio of the lactide / ε-caprolactone copolymer is 4: 6 to 1: 9 out of the drug release is too fast to control drug release There is a problem.

Experimental Example 3

(Drug Release In Vitro Experiment with Copolymer Content)

The stent coated by the method of Example 1 and Comparative Examples 4 to 5 was tested in the same manner as in Experimental Example 2.

Figure 2 is a graph showing the drug release form of the biodegradable polymer film for drug release stents prepared by the method of Example 1 and Comparative Examples 4 to 5 of the present invention. As can be seen in FIG. 2, in Comparative Example 4, the amount of lactide / ε-caprolactone copolymer is small in the mixture for preparing a biodegradable polymer film for drug release stents, thereby increasing the amount of drug release. It is understood that the amount of the copolymer is high so that the amount of drug release is reduced, and thus the drug release form can be controlled according to the content of the copolymer.

Experimental Example 4

(Drug release experiment in vitro according to concentration of biologically active substance)

The stent coated by the method of Example 1 and Comparative Examples 6 to 7 was tested in the same manner as in Experiment 2.

Figure 3 is a graph showing the drug release form of the biodegradable polymer film for drug release stents prepared by the method of Example 1 and Comparative Examples 6 to 7 of the present invention. As can be seen in Figure 3, in the case of Comparative Example 7 biodegradable polymer film preparation for drug release stents the content of paclitaxel is too high due to the excessive amount of drug release, in the case of Comparative Example 6 the amount of drug release due to the high content of the copolymer It is understood that this decreases.

Experimental Example 5

(Drug release ( in vitro ) experiment with saliva coating time)

The stent coated by the method of Example 1 and Comparative Examples 8 to 9 was tested in the same manner as in Experimental Example 2.

Figure 4 is a graph showing the drug release form of the biodegradable polymer film for drug release stents prepared by the method of Example 1 and Comparative Examples 8 to 9 of the present invention. As can be seen in Figure 4, in the case of Comparative Example 9 the salting time is long, the drug release amount is too large, in the case of Comparative Example 8, the salting time is short, it can be seen that the drug release amount is small.

Biodegradable polymer film for drug release stent coated according to the method of the present invention is excellent in flexibility and elastic mechanical properties, and after a certain period of time after the stent treatment is biodegradable and does not require a separate removal surgery, as a stent It prevents restenosis by minimizing the inflammatory response caused, and can slowly release biologically active substances, including restenosis suppressing drugs, in the human body for long-term delivery.

Claims (5)

A biodegradable polymer film for drug release stents prepared from a biodegradable lactide / ε-caprolactone copolymer having a repeating unit of Formula 1 and having a molar ratio of lactide to ε-caprolactone of 4: 6 to 1: 9: [Formula 1]

(Wherein x and y are the molar ratios of each monomer, x is 0.1 to 0.4, y is 0.6 to 0.9, x + y = 1, n is the polymerization degree of a copolymer, 25 or more, Preferably it has a value of 25-30.) In claim 1, Biodegradable polymer film for drug release stents, characterized in that the tensile strength of the 15 to 35 MPa biodegradable polymer film for drug release stents. In claim 1, The biodegradable polymer film for drug release stent, characterized in that the elongation of the biodegradable polymer film for drug release stent is 600 to 800%. (1) 5 to 10% by weight of a biodegradable lactide / ε-caprolactone copolymer having a repeating unit of formula 1 and having a molar ratio of lactide to ε-caprolactone of 4: 6 to 1: 9, biologically active substance Preparing a biodegradable film coating mixture comprising 1 to 30% by weight and a solvent balance; (2) dip-coating the stent into the mixture for 30 to 90 seconds; And, (3) drying the dip-coated stent at room temperature for 20 to 60 hours Biodegradable polymer film coating method for drug release stent comprising: [Formula 1]

(Wherein x and y are the molar ratios of each monomer, x is 0.1 to 0.4, y is 0.6 to 0.9, x + y = 1, n is the polymerization degree of a copolymer, 25 or more, Preferably it has a value of 25-30.) In claim 4, The biologically active substance is a biodegradable polymer film coating method for drug release stent, characterized in that selected from the group consisting of paclitaxel, rapamycin, dexamethasone, and actinomycin-di.

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